9,10-Secoestrane derivatives and their production

ABSTRACT

9,10-Secoestranes, useful as intermediates in the total synthesis of steriods, of the formula   WHEREIN N IS 1 OR 2, R1 is lower alkyl, R2, R3 and R4 are hydrogen, alkoxy or acyloxy, X is free or ketalized carbonyl or free, esterified or etherified hydroxymethylene, and Y is carbonyl or dialkoxymethylene are produced by condensing, in the presence of a basic catalyst,   WHEREIN X, n, R1, R2, R3, R4 have the values given above, and Z is Cl, Br or I, to produce a 9,10-secoestrane of the above formula wherein Y is a free carbonyl group, which can then, if desired, be ketalized to a corresponding compound wherein Y is dialkoxymethylene or like ketal group.

United States Patent [1 1 Eder et al.

[ June 17, 1975 1 9,10-SECOESTRANE DERIVATIVES AND THEIR PRODUCTION {75] Inventors: Ulrich Eder; Gregor Haffer; Jiirgen Ruppert; Gerhard Sauer; Rudolf Wiechert, all of Berlin, Germany [73] Assignee: Schering Aktiengesellschaft, Berlin,

Germany 22 Filed: Oct. 24, 1973 211 App]. No.: 409.235

[30] Foreign Application Priority Data Oct. 25, I972 Germany 2253089 [52] US. Cl. 260/590; 260/340.3; 260/340.5; 260/340.6; 260/3407; 260/3973; 260/397.4;

[51] Int. Cl C07c 49/76; C07c 49/82 [58] Field of Search 260/590, 540, 397.4, 397.3, 260/397.5

[56] References Cited UNITED STATES PATENTS 3,317,566 5/1967 Whitehurst ct al. 260/590 Primary Examiner-D. Horwitz Attorney, Agent, or FirmMillen, Raptes & White [5 7] ABSTRACT 9,10-Secoestranes, useful as intermediates in the total synthesis of steriods, of the formula 2 I (CH wherein n is l or 2, R is lower alkyl, R R and R are hydrogen, alkoxy or acyloxy, X is free or ketalized carbonyl or free, esterified or etherified hydroxymethylene, and Y is carbonyl or dialkoxymethylene are produced by condensing, in the presence of a basic catalyst,

wherein X, n, R,, R R R have the values given above, and Z is Cl, Br or I, to produce a 9,10- secoestrane of the above formula wherein Y is a free carbonyl group, which can then, if desired, be ketalized to a corresponding compound wherein Y is dialkoxymethylene or like ketal group.

14 Claims, No Drawings 1 9,10-SECOESTRANE DERIVATIVES AND THEIR PRODUCTION BACKGROUND OF THE INVENTION This invention relates to a process for the preparation of 9,10-secoestra1ie derivatives.

SUMMARY OF THE INVENTION According to this invention 9.10-secoestranes of the general Formula I wherein n is the integer l or 2; R is lower alkyl; R R and R, are alike or different and each is a hydrogen atom, alkoxy, or acyloxy; X is free or ketalized carbonyl or a free or ketalized carbonyl or a free, esterifled or etherified hydroxymethylene, and Y is Carbonyl or dialkoxymethylene; are produced by condensing a compound of general Formula 11 2 n II wherein 12, R and X have the values given above, in the presence of a basic catalyst, with an w-haloacetophenone of general Formula 111.

III

4 COCH Z wherein R R R R X and Y have the same values as in Formula I.

DETAILED DISCUSSION Preferred compounds of Formula I are those wherein a. n is 1 (Compounds of Formula la);

b. R is methyl or ethyl, especially those of (a);

0. At least one of R R and R preferably R is an esterified or etherified hydroxy, e.g., alkanoyloxy of 2-8 carbon atoms or alkoxy of l-8 carbon atoms, and at least one and preferably both of the remainder are hydrogen atoms, especially those of (a) and (b);

d. X is hydroxymethylene or alkoxymethylene of l-8 carbon atoms, preferably tert.-butoxymethylene, especially those of (a), (b) and (c); and

e. Y is carbonyl or dimethoxymethylene, those of (a), (b). (c) and ((1).

Lower alkyl means alkyl of one to six carbon atoms. Preferred R groups are those of l-4 carbon atoms. e.g., methyl, ethyl, propyl, isopropyl and the butyl groups, especially methyl or ethyl.

R R and R, can be a hydrogen atom, an alkoxy group or an acyloxy group. Preferred such alkoxy groups are those of l-4 carbon atoms, e.g., methoxy. ethoxy, propoxy, isopropoxy, butoxy and tertl-buto xy. Preferred such acyloxy groups are those of l-l2 carbon atoms wherein the acyl group is that of an aliphatic, cycloaliphatic or aromatic, preferably hydrocarbon, e.g., carboxylic acid, of 2-8 carbon atoms. Examples of such acyloxy groups are the acetoxy, propionyloxy. butyryloxy, trimethylacetoxy, hexanoyloxy or other alkanoyloxy. cyclopentylcarboxy or benzoyloxy group.

X can be a free or ketalized carbonyl or hydroxymethylene, which can be free, esterified or etherified, e.g., hydroxymethylene, hydrocarbonoxymethylene or hydrocarboncarbonyloxymethylene. Such ketalized carbonyl groups are dialkoxymethylene as defined for Y or preferably alkylenedioxymethylene groups of 2-6 carbon atoms and with 2-3 carbon atoms in the alkylene chain or a o-phenylenedioxymethylene group, e.g., l,Z-ethylenedioxymethylene, 1,3- propylenedioxymethylene, 2,3- butylenedioxymethylene, 2,2-dimethyl-l ',3 propylenedioxymethylene, 2,4-pentylenedioxymethylene and l,Z-phenylenedioxymethylene. Examples of esterified hydroxymethylene groups are those wherein the ester groups have 1-10 carbon atoms, e.g., carboxylic acid groups, preferably hydrocarbon carboxylic acid ester groups, for example, acetoxy, propionyloxy, butyryloxy, trimethylacetoxy, pentanoyloxy, hex-- anoyloxy, heptanoyloxy, octanoyloxy -andbenzoyloxy. Examples of etherified hydroxymethylene groups are alkoxymethylene groups of l-lO carbon atoms and aralkoxymethylene groups of 7-10 carbon atoms in the alkoxy and aralkoxy group, respectively, e.g., methoxy, ethoxy, propoxy, butoxy, tert.-butoxy, isopropoxy and benzyloxy.

As will be apparent to those skilled in the art, if the compounds of Formula I are to be used as intermediates for the production of steroids, when X is a free, esterified or etherified hydroxymethylene group, the oxy group is preferably of the 17B-stereo configuration, corresponding to the l7B-hydroxy group of a naturally occurring steroid.

Y can be a free carbonyl group or, like X, a ketalized carbonyl group, preferably a dialkoxymethylene group.

especially ymethylene, diethoxymethylene, dipropoxymethylene groups are ordinarily of little if any benefit, particularly l since most of these groups are merely blocking groups which are'subsequently removed to regenerate the free hydroxy or keto group. Therefore, in addition to those R R R,, X and Y groups more precisely defined in the claims hereinafter, equivalent are those bearing one, two, three or more substituentseg. halo, nitro,

4 Formula III to the compounds of Formula II is effected in an inert solvent. Suitable solvents are, for example, polar ethers, e.g., 1,2-dimethoxyethane, 2,2'-

' dimethoxydiethyl ether. tetrahydrofuran and dioxane,

amido, carbamide, primary, sec. or tert.-amino, alkoxy,

'alkanoyloxy, mercapto, sulfato, etc.; the cyclic counterparts of alkylgroups, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl'. aryl analogs of phenyl groups, e.g., naphthyl, p-tolyl, sym.-xylyl; and sulfonic ester analogs of carboxylic ester groups, e.g., methanesulfonyloxy, ethanesulfonyloxy, p-toluenesulfonyloxy and benzenesulfonyloxy.

In addition to the species of the examples hereinafter, the following are illustrative examples of the compounds of this invention: 3,17B-diacetoxy-9,l0-seco-l,3,5( l0),8( l4)- estratetraene-6,9-dione,

3-methoxy-l7B-benzyloxy-9,10-seco-l,3,5(I0),8(14)- sodium tert.-butylate, potassium tert.-butylate, lithium amide, tetramethylammonium hydroxide and trimethylbenzylammonium hydroxide, in an inert solvent. It is advantageous in this reaction to employ at dan of Formula II, in order to form the carbanion, and to bind the hydrogen halide liberated by the reaction with the haloacetophenone of Formula III. A somewhat elevated temperature, e.g., 30C. up to the boiling temleast 1 mole of basic catalyst per mole of tetrahydroinperature of the solvent, is preferably employed, along with a protective gas atmosphere such as, for example, nitrogen or argon.

The chemical addition of the haloacetophenones of secondary or tertiary alcohols, e.g., isopropanol, 2- butanol and tert.-butanol, and dipolar aprotic solvents, e.g., dimethylformamide, N-methylacetamide. N- methylpyrrolidone and hexamethylphosphoric triamide. It is also possible to use mixtures of the abovementioned solvents and relatively nonpolar solvents, e.g., benzene and toluene.

When X of the starting compounds of general Formula II is a free hydroxymethylene group, it is advantageous, in order to obtain higher yields, to first react it with a vinyl ether, e.g., methyl or ethyl or other alkyl vinyl ether. In this case, compounds otherwise corresponding to those of Formula II are obtained as intermediates in which X is an (l-alkoxyethyl)- oxymethylene group, e.g., (l-ethoxyethyl)- oxymethylene. This group is then split off again after the reaction has been accomplished during the working up of the reaction mixture.

The condensation of the haloacetophenones of Formula III to the tetrahydroindan derivatives of Formula II preferably conducted at a reaction temperature of from -50C. to +50C., preferably 25C. to +2SC.

It is surprising that the condensation of the compounds of Formula II with the haloacetophenones produces the 6-oxo-9,10-secoestrane derivatives of Formula I in high yields, because it is known that the condensation of compounds of general Formula I with the corresponding phenethyl halides produces 9,10- secoestrane derivatives only to very low yields. See J. Chem. Soc, I970, l0l8.

The thus-produced compounds of general Formula I wherein Y is a free carbonyl group can optionally then be ketalized, e.g., with a lower alcohol, thus obtaining compounds of Formula I wherein the group Y is ketal' ized keto, e.g., dialkoxymethylene, group. This ketalization is conducted in a conventional manner, preferably by reacting the keto compound with the selected alcohol in the presence of an acidic catalyst. Suitable alcohols are, for example, lower alkanols of l4 carbon atoms, e.g., methanol, ethanol, propanol and butanol. Suitable acidic catalysts include mineral acids, e.g., hydrochloric acid, sulfuric acid and perchloric acid; sulfonic acids, e.g., methanesulfonic acid; Lewis acids, e.g., boron trifluoride; and phenols, e.g., p-nitrophenol and 2,4-dinitrophenol. The ketalization is especially successful when a water-binding agent is added to the reaction mixture, e.g., anhydrous sodium sulfate, magnesium sulfate and calcium sulfate. Other waterbinding agents include orthoformic acid esters or acetone dialkyl ketals of the alcohols employed for the ketalization. The ketalization is preferably conducted at a reaction temperature of between 20C. and +50C.

This ketalization takes place surprisingly selectively on the 0x0 group in the'6-position and the 0x0 group in the 9-position is substantially unaffected.

The compounds of general Formula I produced in accordance with the process of this invention are valuable intermediates for the production of polycyclic compounds. They are especially suitable for the manufacture of pharmacologically effective steroids by a total synthesis.

The following reaction scheme illustrates the use of compounds of Formula I in a total steroid synthesis:

Thus, as disclosed in our copending application Ser." No. 409,234, filed Oct. 24, 1973, of the same title, the disclosure of which is incorporated by reference, heating the 9,IO-secoestranes of Formula-l in benzene or toluene in the presence ofa catalytic amount of p-toluenesulfonic acid or other acidic catalyst while simultaneously removing the thusformed water or alcohol by distillation produces compoundsof Formula IV. The latter can then be hydrogenated under pressure in an alcoholic solution with hydrogen in the presence of a palladium catalyst to producecompounds of Formula V 1 The compounds of Formula V can be oxidized to the compounds of Formula VI inacetone at '10C. to C. with chromosulfu'ric acid. The conversion of compounds of Formula V1 to pharmacologically active steroids can be accomplished in a conventional manner, e.g., by cyclising the compounds of formula VI to the corresponding estrane derivatives, optionally hydrolysing the estrane-esters or estrane-ethers and oxidizing 17,8-hydroxy-estrane-derivatives under conventional conditions (German Pat. No. 1,231,699).

The compounds of the general formula 1 may be used as intermediates for the production of pharmacologlcally. active estrane derivatives e.g., estrone, estradiole, 2-hydroxyestrone (Steroids 4, 1964,267), lhydroxy-estradiole (Arzneimittel-Forschung l 1966,1518) or 3-desoxy-estrone (US. Pat. No. 3,081,316).

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The

following preferred specific embodiments are, therefore, to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.

EXAMPLE 1 H 20 g. of lB-tert-butoxy-7aB-methyl-5,6,7,7a-tetrahydroihdan-S-one is dissolved in 250 ml. of absolute tetrahydr ofuran. The reaction flask is then flushed with argon. After adding 2.35 g. of sodium hydride, the reaction mixture is refluxed for 10 hours, cooled to lOC., and combined dropwise with a solution of 22.5 g. of 3'-methoxy-l-bromoacetophenone in 100 m1. of absolute tetrahydrofuran.

After a reaction time of 16 hours at 10C. to 0C., the solvent is distilled off under vacuum, and the reaction mixture is extracted with ether after adding 250 ml. of saturated sodium chloride solution. The ether extract is washed, dried, and concentrated under vacuum. The residue is purified by chromatography, recrystallized from diisopropyl ether, and the product is 25.1 g. of 3-methoxy- 1 7,8-tert.-butoxy-9, 1 O-seco- 1,3,5(10),8(14)-estratetraene-6.9-dione, m.p. 7576.5C.

Y 1 1,?" 0.9 (chloroform; c 1),

' EXAMPLE 2 1 1.3 g. of 1B-tert.-butoxy-7aB-ethy1-5,6,7,7a-tetrahydroindan-S-one is reacted according to Example 1 in 150 ml. of absolute dimethoxyethane with 1.3 g. of sodium hydride. Under ice cooling, a solution of 12.4 g.

of 3-methoxy-l-bromoacetophenone in ml. of absolute dimethoxyethane is added dropwise within 10 minutes; subsequently, the reaction mixture is stirred for 16 hours under ice cooling.

The reaction product is worked up and purified as described in Example 1, thus obtaining 11.9 g. of 3- 'methoxy-l7B-tert.-butoxy-18-methyl-9,l0-secol',3,5( 10),8( l4)-estratetraene-6,9-dione as: a colorless oil. IR bands at 5.96 p. and 6.05 ,u. [a]1) =-O.2 (chloroform; 0 1).

EXAMPLE 3 EXAMPLE 4 10 g. of lB-hydroxy-7a/3-methyl-5,6,7 7u-tetrahydroindan-S-one is dissolved in 100 ml. of absolute dimethoxyethane. and 6 g. of freshly distilled cthylvinyl ether and l() mg. of p-toluenesulfonic acid are added thereto. The mixture is agitated for one hour at room temperature.

Thereafter, the excess ethylvinyl ether is distilled off under vacuum, and 1.7 g. of sodium hydride is added. After a reaction time of 15 hours at 70 C., the mixture is cooled to 5 C. and, within 20 minutes. a solution of'l6.5 g. of 3-methoxy-l-bromoacetophenone in 50 ml. of absolute dimethoxyethane is added dropwise thereto. After a reaction period of lo hours under ice cooling, the mixture is gently acidified with lN hydrochloric acid to a pH of 3. and agitated for 30 minutes at room temperature.

The light-brown product obtained after conducting the usual working-up operation is chromatographed on a silica gel column for purification purposes. thus ob- ;taining 15.8 g. of l7B-hydroxy-3-methoxy-9,l0-seco- .l,3,5( l),8( l4)-estratetraene-6,9-dione as a colorless oil. lR bands at 5.95 p. and 6.02 ,u.. [01],, +l3.5

(chloroform; c 1).

EXAMPLE disclosed in Example 4, and the product is 6.1 g. of 17- B-hydroxy-3-methoxyl 8-methyl-9, lO-secol,3,5( l0),8( l4)-estratetraene-6,9-dione as a colorless oil. IR bands at 5.96 [.L and 6.04 ,u. [a],, =+9.2(chloroform; l).

EXAMPLE 6 10 g. of 3-methoxy-l7B-tert.-butoxy-9,lO-secol ,3,5( l0),8( l4)-estratetraene-6,9-dione is dissolved in "100 ml. of absolute methanol and 10 ml. of trimethyl 'orthoformate, and the solution is cooled to 0 C. Then, 50 mg. of -toluenesulfonic acid is added and the mix-' ture is agitated for hours under ice cooling. Thereafter, the mixture is poured into 500 ml. of dilute sodium bicarbonate solution and extracted with ether. The

ether phase is washed, dried and concentrated under vacuum, thus obtaining 12.3 g. of 3,6,6-trimethoxy- 17B-tert.-butoxy-9,lO-seco-l,3,5( l0),8( 14)- estratetraen-9-one as a colorless oil. IR band at 6.04 pt,

no band at 5.96 ,u..

EXAMPLE 7 1 Under the conditions of example 1, lB-tertbutoxy7aB-methyl-5,6,7,7atetrahydroindan-S-one can condensed with w-bromo-3,5-dimethoxyacetophenone to give 1,3-dimethoxy-l7/3-tert.-butoxy- .,9.lO-seco-l,3,5(l0),8(14)-estratetraene-6.9-dione which can be ketalised under the conditions of example 6 to the l,3,6,6-tetramethoxy-17B-tert.-butyloxy-9,l0- seco-l ,3,5( l0),8( l4)-estratetraen-9-one.

EXAMPLE 8 Under the conditions of example l lfi-terL-butoxy- 7aB-methyl-5.6,7,7a tetrahydroindan -5-one can be condensed withw-bromo-3,4-dimethoxyacetophenone to give 2,3-dimethoxy-l7B-tert.-butoxy- 9,lO-seco-l ,3,5( l0),8( l4)-estratetraene-6,9-dione.

The preceding examples can be repeated with similar success by substituting and generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. i

What is claimed is:

l. A 9.10-secoestrane formula wherein R is lower alkyl; R R and R each is a hydrogen atom or alkoxy of 1-4 carbon atoms; X is carbonyl, dialkoxymethylene wherein the alkoxy groupsv each contain l-4 carbon atoms, hydroxymethylene, alkoxymethylene wherein the alkoxy group contains l-lO carbon atoms or aralkoxymethylene wherein the aralkoxy group contains 71O carbon atoms; andn Y is carbonyl or dialkoxymethylene.

2. A compound of claim 1 wherein R, is methyl or ethyl.

3. A compound of claim 1 wherein R is alkoxy of l-8 carbon atoms and R and R are hydrogen atoms.

4. A compound of claim 1- wherein X is hydroxymethylene or alkoxym ethylene wherein alkoxy is of l-8 carbon atoms. i

5. A compound of claim 1 wherein dimethoxymethylene. g

6. A compound of claim 1 wherein R ismethyl or ethyl, R is alkoxy of l-8 carbon atoms and R and R are hydrogen atoms, X-is hydroxymethylene or alkoxymethylene wherein alkoxy is of l-8 carbon atoms, and Y is carbonyl or dimethoxymethylene.

7. The compound :ofclaim-l, 3-methoxy-l7B -tert.- butoxy-9, IO-seco-l ,3,5( 10 );8( l4 )-est:ratetraene-6,9--.

dione.

8. The compound of claim 1, 3-methoxy l7B:tert.- butoxy-l8-met hyl-9, 10 seco l,3,5( 1Q),8.( l4); estratetraene-6,9-dione. y I I I 9. The compound of claim 1, l7B-tert.-butoxy:9, l0- seco-l,3,5(10),8 (l4)restratetraene-6,9-d ione. I

10. The compound of claim l, 17B-hydroxy-3- methoxy-9,l0-seco-l,3,5( l0),8( l4)-estratetraene,6,9- dione. ii I l i 11. The compound of claim 1, 17B-hyd roxy-3- methoxy-l 8-methyl-9,lO-seco -l ,3,5 l0),8( l4)- estratetraene-6,9-dione.

12. The compound of claim 1, 3,6,6-trimethoxy- 1 7B- tert.-butoxy-9,lO-secol ,3,5( l0),8( l4l-estratetraen- 9-one.

Y carbonyl or 13. A process for the preparation of 9 l()-secoestrane derivatives of claim 1 which comprises condensing, in the presence of a basic catalyst. 21 compound of the formula wherein n, R and X have the values given above, with an w-haloacetophenone of the formula COCH Z 

1. A 9.10-SECOESTRANE FORMULA
 2. A compound of claim 1 wherein R1 is methyl or ethyl.
 3. A compound of claim 1 wherein R4 is alkoxy of 1-8 carbon atoms and R2 and R3 are hydrogen atoms.
 4. A compound of claim 1 wherein X is hydroxymethylene or alkoxymethylene wherein alkoxy is of 1-8 carbon atoms.
 5. A compound of claim 1 wherein Y is carbonyl or dimethoxymethylene.
 6. A compound of claim 1 wherein R1 is methyl or ethyl, R4 is alkoxy of 1-8 carbon atoms and R2 and R3 are hydrogen atoms, X is hydroxymethylene or alkoxymethylene wherein alkoxy is of 1-8 carbon atoms, and Y is carbonyl or dimethoxymethylene.
 7. The compound of claim 1, 3-methoxy-17 Beta -tert.-butoxy-9, 10-seco-1,3,5(10),8(14)-estratetraene-6,9-dione.
 8. The compound of claim 1, 3-methoxy-17 Beta -tert.-butoxy-18-methyl-9,10-seco-1,3,5(10),8(14)-estratetraene-6,9-dione.
 9. The compound of claim 1, 17 Beta -tert.-butoxy-9,10-seco-1,3, 5(10),8(14)-estratetraene-6,9-dione.
 10. The compound of claim 1, 17 Beta -hydroxy-3-methoxy-9,10-seco-1,3,5(10),8(14)-estratetraene-6,9-dione.
 11. The compound of claim 1, 17 Beta -hydroxy-3-methoxy-18-methyl-9,10-seco-1,3,5(10),8(14)-estratetraene-6,9 -dione.
 12. The compound of claim 1, 3,6,6-trimethoxy-17 Beta -tert.-butoxy-9,10-seco-1,3,5(10),8(14)-estratetraen-9-one.
 13. A process for the preparation of 9,10-secoestrane derivatives of claim 1 which comprises condensing, in the presence of a basic catalyst, a compound of the formula
 14. A process according to claim 13 wherein R1 is methyl or ethyl, R4 is alkoxy of 1-8 carbon atoms and R2 and R3 are hydrogen atoms, and X is hydroxymethylene or alkoxymethylene wherein alkoxy is of 1-8 carbon atoms. 